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Infectious Diseases - Tuberculosis - Fast Facts | NEJM Resident 360
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis bacteria. Tuberculosis (TB) is one of the most common infections worldwide (>2 billion people may have latent TB infection). In the United States, the rate of TB cases has been declining since 1992 as a result of the establishment of tuberculosis control programs, implementation of screening programs for patients at high risk for the disease, and advancement of diagnostic techniques that allow rapid diagnosis. In this section, we cover the diagnosis and management of:
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Active Tuberculosis Infection
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Latent Tuberculosis Infection
Active Tuberculosis Infection
Active tuberculosis is characterized by infection with Mycobacterium tuberculosis and associated signs and symptoms of disease. Primary infection occurs when airborne M. tuberculosis is inhaled and travels through the respiratory tract until it reaches the alveoli. In most individuals, the immune system can control this infection without treatment (see Latent Tuberculosis Infection below). In some patients, particularly those with compromised immune systems (e.g. HIV infection), the primary infection can progress to pneumonia and can even disseminate to cause extrapulmonary tuberculosis (in 10%–40% of cases). TB is a great imitator: it can affect any organ in the body (e.g., brain, heart, kidney, eye, lymph node, skin), has varied clinical manifestations, and requires a high index of suspicion.
Presentation
The typical presentation of active pulmonary TB includes pulmonary symptoms and constitutional symptoms:
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chronic cough (>2 weeks)
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sputum production
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hemoptysis
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chest pain
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dyspnea
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appetite loss
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weight loss
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fever
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night sweats
If TB is suspected, the patient should be placed in a negative-pressure isolation room. Airborne precautions should be undertaken by those in contact with the patient to avoid transmission. Contact tracing of confirmed cases should be performed by the public health department.
Diagnosis
The following table indicates some patient groups that warrant an evaluation of pulmonary TB:
(Source: Controlling Tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recommendations and Reports 2005).
Testing recommendations and considerations:
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Obtain three induced sputum samples for acid-fast bacilli (AFB) smear microscopy. A single AFB smear has lower sensitivity for ruling out pulmonary disease.
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Consider bronchoscopy in patients who cannot provide induced sputum. The advantage of bronchoscopy is that a biopsy can be obtained.
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Culture for M. tuberculosis is the gold standard microbiologic test.
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Perform a diagnostic nucleic acid amplification test (NAAT) on an initial respiratory specimen. A negative NAAT can help rule out a false positive AFB smear. NAAT has higher sensitivity than AFB smear in some situations (e.g., concurrent HIV infection, where the disease can be paucibacillary and has higher chance of negative AFB smear). TB tests on the market are the Cepheid Xpert MTB/RIF test (can also detect rifampin resistance) and the Hologic Amplified Mycobacteria Tuberculosis Direct (MTD) test.
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Interferon-gamma–release assay (IGRA) test and tuberculin skin tests can be negative in acute disease and in immunocompromised patients.
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Elevated adenosine deaminase levels can be seen in TB-infected body fluids, such as pleural effusion, cerebrospinal fluid, ascites, or pericardial effusion.
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Chest imaging typically shows upper-lobe cavitary disease.
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Histopathological examination of biopsies shows granulomas. Culture, AFB smear, and NAAT can be performed on extrapulmonary specimens for diagnosis.
Treatment
M. tuberculosis during treatment exhibits a biphasic decline, during which actively replicating bacilli are killed initially while a nonreplicating subpopulation persists and requires longer treatment. Some bacilli may be sequestered by the immune system and inaccessible to antibiotics. Consequently, treatment is split into the intensive phase (~2 months), followed by a continuation phase (~4 months) to maximally eradicate bacilli. Treatment regiments will vary depending on whether infection is with drug-susceptible or drug-resistant TB. Drug-resistant TB is defined as resistance to at least one of the first-line antimycobacterial drugs.
CDC recommendations for drug-susceptible TB regimens are shown below. Please see the CDC website for more information on drug-resistant TB.
Drug-Susceptible TB Disease Treatment Regimens
Abbreviations: DOT = directly observed therapy; EMB = ethambutol; HIV = human immunodeficiency virus; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin.
a Other combinations may be appropriate in certain circumstances; additional details are provided in the Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.
b When DOT is used, drugs may be given 5 days per week and the necessary number of doses adjusted accordingly. Although there are no studies that compare 5 with 7 daily doses, extensive experience indicates this would be an effective practice. DOT should be used when drugs are administered less than 7 days per week.
c Based on expert opinion, patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week) continuation phase.
d Pyridoxine (vitamin B6), 25–50 mg/day, is given with INH to all persons at risk of neuropathy (e.g., pregnant women; breastfeeding infants; persons with HIV; patients with diabetes, alcoholism, malnutrition, or chronic renal failure; or patients with advanced age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
e Alternatively, some U.S. TB control programs have administered intensive-phase regimens 5 days per week for 15 doses (3 weeks), then twice weekly for 12 doses.
Note: Use of once-weekly therapy with INH 900 mg and rifapentine 600 mg in the continuation phase is not generally recommended. In uncommon situations where more than once-weekly DOT is difficult to achieve, once-weekly continuation phase therapy with INH 900 mg plus rifapentine 600 mg may be considered for use only in HIV uninfected persons without cavitation on chest radiography.
(Source: Treatment for TB Disease. Centers for Disease Control and Prevention 2015.)
Treatment of extrapulmonary TB is similar to that of pulmonary TB, but the duration of therapy is usually longer than 6 months. Patients with TB meningitis, and sometimes TB pericarditis require glucocorticoids as an adjunct to antimicrobial therapy.
Avoid fluoroquinolones in cases of pneumonia in which TB is suspected, because these antibiotics are active against TB. See below for a figure illustrating the various mechanisms of anti-TB drugs.
Sites and Mechanisms of Action of Antimycobacterial Agents
(Source: Treatment of Tuberculosis. N Engl J Med 2015.)
Latent Tuberculosis Infection
Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest active disease. After initial exposure to M. tuberculosis, some people develop an active infection while others’ immune systems contain the bacilli within macrophages, granuloma, and lymph nodes, leading to LTBI. LTBI is usually asymptomatic. An estimated 5%–15% of immunocompetent individuals with LTBI develop active infection during their lifetimes, and the risk increases in patients with compromised immune systems, either because of age or concomitant illnesses.
Diagnosis
Most cases of TB resulting from reactivated LTBI can be prevented with antibiotics. Therefore, it is important to screen for infections in populations at high risk for either acquiring LTBI or reactivation or both.
Risk factors for LTBI include:
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close contact with someone with infectious TB
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born in a TB-endemic country
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homelessness
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injection drug use
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immunosuppression (e.g., HIV infection, TNF-α inhibitors, organ transplantation)
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end-stage renal disease on hemodialysis
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incarceration
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health care workers
One of the following tests can be used for diagnosis in a patient who does not have symptoms of active TB and who has no signs of active TB on chest radiograph. These tests may be negative in active TB and should not be used to rule out active TB. They also poorly predict progression to active TB.
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tuberculin skin test (TST)
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TST is inexpensive but has poor specificity in populations vaccinated with bacille Calmette–Guérin (BCG) and poor sensitivity in immunocompromised hosts. Be aware of booster phenomenon (positive result on retesting).
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Interpretation of TST at 2–3 days after administration depends on risk of infection, risk of progression, and benefit of treatment (see figure below for interpretation in various populations).
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interferon-gamma–release assay (IGRA) test
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Currently available IGRAs include the QuantiFERON-TB Gold (QFT, Qiagen) In-tube assay and the T-SPOT.TB assay (Oxford Immunotec).
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IGRA is more specific than the tuberculin skin test (because it is not affected by prior BCG vaccination) but is more expensive and may not be widely available. IGRAs can be indeterminant in patients with poor immune response.
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Diagnostic Testing for Latent TB Infection
(Source: Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infec Dis 2017.)
The Infectious Diseases Society of America (IDSA) recommends IGRA rather than TST for LTBI testing in individuals aged 5 years and older who are likely to be infected with M. tuberculosis, have low or intermediate risk of disease progression, and either have a history of BCG vaccination or are unlikely to follow up for TST reading.
Treatment
Although patients with LTBI typically are asymptomatic and not contagious, the potential for reactivation places them at risk of becoming sick and is a public health concern. Thus, treatment of LTBI is essential for controlling and eliminating TB. The CDC’s recommended treatment regimens for latent TB are shown in the following table. Shorter rifamycin-based regimens are preferable to longer isoniazid monotherapy. Note, these recommendations must be modified if the patient has been in contact with an individual with drug-resistant TB. Rule out active TB before starting these regimens.